A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells

Byun, Jun‐Kyu; Choi, Youn‐Hee; Kim, Jihyun; Jeong, Ji Yun; Jeon, Hui-Jeon; Kim, Mi-Kyung; Hwang, Ilseon; Lee, Shin-Yup; Lee, You Mie; Lee, Inkyu; Park, Keun-Gyu

doi:10.1016/j.celrep.2017.06.066

Cited by 71 publications

(65 citation statements)

References 32 publications

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“…The decrease in intracellular levels of both glutamine and glutamate under SESN2down-regulated conditions and their increase post-SESN2 overexpression indicated that Sestrin2 did have a link to the glutamine levels in cells, but certainly it did not regulate the conversion of glutamine to glutamate because there was no accumulation of glutamine, which would have normally occurred if the conversion of glutamine to glutamate was blocked. A recent study has shown that SESN2 promotes survival of cancer cells by inhibiting mTORC1 and activating mTORC2 signaling under depletion of glutamine [20]. Our studies showing silencing of SESN2 expression under glucose limitation (adequate glutamine) negatively regulating mTORC2 while activating mTORC1 suggests that under differential metabolic stressors, SESN2 may act as a sensor that promotes cancer cell survival by positively regulating mTORC2, which in turn regulates mTORC1.…”

Section: Discussionsupporting

confidence: 50%

“…Moreover, the same study also suggests SESN2 as a possible methionine sensor under leucine starvation, which may further influence mTOR activation . Apart from acting as a leucine sensor, SESN2 has been recently reported to induce a positive feedback loop with mTORC2 for survival of glutamine‐deprived cancer cells . We enquired if SESN2 can induce metabolic reprogramming under glucose starvation (provided glutamine is abundant) in cancer cells and if so how that impacts PGC‐1α levels.…”

Section: Introductionmentioning

confidence: 89%

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Sestrin2 facilitates glutamine‐dependent transcription of PGC‐1α and survival of liver cancer cells under glucose limitation

2018

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Differential utilization of metabolites and metabolic plasticity can confer adaptation to cancer cells under metabolic stress. Glutamine is one of the vital and versatile nutrients that cancer cells consume avidly for their proliferation, and therefore mechanisms related to glutamine metabolism have been identified as targets. Recently, sestrin2 (SESN2), a stress-inducible protein, has been reported to regulate survival in glutamine-depleted cancer cells; based on this, we explored if SESN2 could regulate glutamine metabolism during glucose starvation. This report highlights the role of SESN2 in the regulation of glutamine-dependent activation of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) under glucose scarcity in liver cancer cells (HepG2). We demonstrate that down-regulation of SESN2 induces a decrease in the levels of intracellular glutamine and PGC-1α under glucose deprivation, concomitant with a decline in cell survival, but no effect was observed on the invasive or migration potential of the cells. Under similar metabolic conditions, SESN2 forms a complex with c-Jun N-terminal kinase (JNK) and forkhead box protein O1 (FOXO1). Absence of SESN2 or inhibition of JNK reduces nuclear translocation of FOXO1, consequently causing transcriptional inhibition of PGC-1α. Notably, our observations demonstrate a reduction in cell viability under high glutamine and low glucose conditions during SESN2 down-regulation that could be rescued on JNK inhibition. To recover from acetaminophen-induced mitochondrial damage, SESN2 was crucial for glutamine-mediated activation of PGC-1α in HepG2 cells. Collectively, we demonstrate a novel role of SESN2 in mediating activation of PGC-1α by modulating glutamine metabolism that facilitates cancer cell survival under glucose-limited metabolic conditions.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 89%

Sestrin2 facilitates glutamine‐dependent transcription of PGC‐1α and survival of liver cancer cells under glucose limitation

2018

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“…It is interesting to note that glutamine depletion decreases mTORC1 activity while increasing mTORC2 activity [54,141]. This differential regulation of mTORC1 and mTORC2 is mediated by sestrin2 and allows survival of these cancer cells by maintenance of energy and redox balance [141]. However, inhibition of glutaminase or GDH did not affect Akt phosphorylation while it diminished mTORC1 activation [29].…”

Section: Glutamine Metabolismmentioning

confidence: 99%

“…mTORC2 also responds to levels of glutamine or its catabolites. It is interesting to note that glutamine depletion decreases mTORC1 activity while increasing mTORC2 activity [54,141]. This differential regulation of mTORC1 and mTORC2 is mediated by sestrin2 and Glutamine is a versatile molecule, as it serves as an alternative carbon source for energy production and its carbon and nitrogen are also used for biosynthetic reactions [130].…”

Section: Glutamine Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

162

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…Mitochondrial proficiency and ROS detoxification are critical for cancer cell viability 26 , and proliferating cancer cells must preserve intracellular ATP and NADPH levels through mitochondrial oxidative phosphorylation and the prevention of excessive ROS accumulation 27 . In silico analyses of the DEGs also suggested that the results were in line with mitochondrial dysfunction during the first period.…”

Section: Discussionmentioning

confidence: 99%

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

Ogata

Makino

Ishizuka

et al. 2020

Sci Rep

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to increase intramuscular fat accumulation, Japanese Black beef cattle are commonly fed a high-grain diet from 10 to 30 months of age. Castrated and fistulated cattle (n = 9) were fed a high-concentrate diets during the early, middle, and late stages consecutively (10-14, 15-22, 23-30 months of age, respectively). Ruminal pH was measured continuously, and rumen epithelium and fluid samples were collected on each stage. The 24-h mean ruminal pH during the late stage was significantly lower than that during the early stage. Total volatile fatty acid (VFA) and lactic acid levels during the late stage were significantly lower and higher, respectively, than those during the early and middle stages. In silico analysis of differentially expressed genes showed that "Oxidative Phosphorylation" was the pathway inhibited most between the middle and early stages in tandem with an inhibited upstream regulator (PPARGC1A, also called PGC-1α) but the most activated pathway between the late and middle stages. these results suggest that mitochondrial dysfunction and thereby impaired cell viability due to acidic irritation under the higher VFA concentration restored stable mitochondrial oxidative phosphorylation and cell viability by higher lactic acid levels used as cellular oxidative fuel under a different underlying mechanism in subacute ruminal acidosis. A high-grain diet promotes the growth, productivity, and quality of meat or milk production in beef and dairy cattle. On a high-grain diet, organic acids such as volatile fatty acids (VFAs) and lactic acid accumulate in the rumen 1,2. Ruminal pH is critical in the maintenance of normal, stable fermentation, microbial populations, and absorptive function 2-4 , and is determined by the balance between acid production by microbes and acid removal by absorption, neutralization, and clearance 1,5,6 , in a host-microbiome interaction 7. The occurrence of subacute ruminal acidosis (SARA) defined by a rumen pH <5.6 is due to the non-physiological accumulation of VFAs, while ruminal acidosis defined by a rumen pH <5.0 is associated with accumulated lactic acid in the rumen 2. Several short-(days) or mid-term (weeks) studies have shown that SARA or rumen acidosis challenges affected the rumen epithelial structure, gene expression, and transcriptomes 8-10. For example, in one study, 3 weeks of a high-grain diet (65% grain) compromised the structural integrity and led to the appearance of undifferentiated cells near the stratum corneum of the rumen papillae in non-lactating dairy cattle 8. In another, the rumen papillae in dairy cattle fed a total mixed ration had increased epithelial desquamation and sloughing scores during early lactation, as well as upregulation of genes encoding desmosome assembly (despoglein1 and corneodesmosin), epidermal growth factor (EGF) signaling (epiregulin), transforming growth factor β (TGFB)

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A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells

Cited by 71 publications

References 32 publications

Sestrin2 facilitates glutamine‐dependent transcription of PGC‐1α and survival of liver cancer cells under glucose limitation

Sestrin2 facilitates glutamine‐dependent transcription of PGC‐1α and survival of liver cancer cells under glucose limitation

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle

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